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The Hypoglycemic Effect of Berberine and Berberrubine Involves Modulation of Intestinal Farnesoid X Receptor Signaling Pathway and Inhibition of Hepatic Gluconeogenesis.
Sun, Runbin; Kong, Bo; Yang, Na; Cao, Bei; Feng, Dong; Yu, Xiaoyi; Ge, Chun; Feng, Siqi; Fei, Fei; Huang, Jingqiu; Lu, Zhenyao; Xie, Yuan; Yang, Chung S; Guo, Grace L; Wang, Guangji; Aa, Jiye.
Afiliación
  • Sun R; Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China (R.S., D.F., X.Y., C.G., S.F., J.H., Z.L., Y.X., G.W., J.A.); Department of Pharmacology and Toxicology (B.K., G.L.G.) and Department of
  • Kong B; Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China (R.S., D.F., X.Y., C.G., S.F., J.H., Z.L., Y.X., G.W., J.A.); Department of Pharmacology and Toxicology (B.K., G.L.G.) and Department of
  • Yang N; Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China (R.S., D.F., X.Y., C.G., S.F., J.H., Z.L., Y.X., G.W., J.A.); Department of Pharmacology and Toxicology (B.K., G.L.G.) and Department of
  • Cao B; Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China (R.S., D.F., X.Y., C.G., S.F., J.H., Z.L., Y.X., G.W., J.A.); Department of Pharmacology and Toxicology (B.K., G.L.G.) and Department of
  • Feng D; Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China (R.S., D.F., X.Y., C.G., S.F., J.H., Z.L., Y.X., G.W., J.A.); Department of Pharmacology and Toxicology (B.K., G.L.G.) and Department of
  • Yu X; Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China (R.S., D.F., X.Y., C.G., S.F., J.H., Z.L., Y.X., G.W., J.A.); Department of Pharmacology and Toxicology (B.K., G.L.G.) and Department of
  • Ge C; Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China (R.S., D.F., X.Y., C.G., S.F., J.H., Z.L., Y.X., G.W., J.A.); Department of Pharmacology and Toxicology (B.K., G.L.G.) and Department of
  • Feng S; Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China (R.S., D.F., X.Y., C.G., S.F., J.H., Z.L., Y.X., G.W., J.A.); Department of Pharmacology and Toxicology (B.K., G.L.G.) and Department of
  • Fei F; Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China (R.S., D.F., X.Y., C.G., S.F., J.H., Z.L., Y.X., G.W., J.A.); Department of Pharmacology and Toxicology (B.K., G.L.G.) and Department of
  • Huang J; Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China (R.S., D.F., X.Y., C.G., S.F., J.H., Z.L., Y.X., G.W., J.A.); Department of Pharmacology and Toxicology (B.K., G.L.G.) and Department of
  • Lu Z; Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China (R.S., D.F., X.Y., C.G., S.F., J.H., Z.L., Y.X., G.W., J.A.); Department of Pharmacology and Toxicology (B.K., G.L.G.) and Department of
  • Xie Y; Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China (R.S., D.F., X.Y., C.G., S.F., J.H., Z.L., Y.X., G.W., J.A.); Department of Pharmacology and Toxicology (B.K., G.L.G.) and Department of
  • Yang CS; Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China (R.S., D.F., X.Y., C.G., S.F., J.H., Z.L., Y.X., G.W., J.A.); Department of Pharmacology and Toxicology (B.K., G.L.G.) and Department of
  • Guo GL; Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China (R.S., D.F., X.Y., C.G., S.F., J.H., Z.L., Y.X., G.W., J.A.); Department of Pharmacology and Toxicology (B.K., G.L.G.) and Department of
  • Wang G; Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China (R.S., D.F., X.Y., C.G., S.F., J.H., Z.L., Y.X., G.W., J.A.); Department of Pharmacology and Toxicology (B.K., G.L.G.) and Department of
  • Aa J; Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China (R.S., D.F., X.Y., C.G., S.F., J.H., Z.L., Y.X., G.W., J.A.); Department of Pharmacology and Toxicology (B.K., G.L.G.) and Department of
Drug Metab Dispos ; 49(3): 276-286, 2021 03.
Article en En | MEDLINE | ID: mdl-33376148
Our previous study suggests that berberine (BBR) lowers lipids by modulating bile acids and activating intestinal farnesoid X receptor (FXR). However, to what extent this pathway contributes to the hypoglycemic effect of BBR has not been determined. In this study, the glucose-lowering effects of BBR and its primary metabolites, berberrubine (M1) and demethyleneberberine, in a high-fat diet-induced obese mouse model were studied, and their modulation of the global metabolic profile of mouse livers and systemic bile acids was determined. The results revealed that BBR (150 mg/kg) and M1 (50 mg/kg) decreased mouse serum glucose levels by 23.15% and 48.14%, respectively. Both BBR and M1 markedly modulated the hepatic expression of genes involved in gluconeogenesis and metabolism of amino acids, fatty acids, and purine. BBR showed a stronger modulatory effect on systemic bile acids than its metabolites. Moreover, molecular docking and gene expression analysis in vivo and in vitro suggest that BBR and M1 are FXR agonists. The mRNA levels of gluconeogenesis genes in the liver, glucose-6-phosphatase and phosphoenolpyruvate carboxykinase, were significantly decreased by BBR and M1. In summary, BBR and M1 modulate systemic bile acids and activate the intestinal FXR signaling pathway, which reduces hepatic gluconeogenesis by inhibiting the gene expression of gluconeogenesis genes, achieving a hypoglycemic effect. BBR and M1 may function as new, natural, and intestinal-specific FXR agonists with a potential clinical application to treat hyperglycemia and obesity. SIGNIFICANCE STATEMENT: This investigation revealed that BBR and its metabolite, berberrubine, significantly lowered blood glucose, mainly through activating intestinal farnesoid X receptor signaling pathway, either directly by themselves or indirectly by modulating the composition of systemic bile acids, thus inhibiting the expression of gluconeogenic genes in the liver and, finally, reducing hepatic gluconeogenesis and lowering blood glucose. The results will help elucidate the mechanism of BBR and provide a reference for mechanism interpretation of other natural products with low bioavailability.
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Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Berberina / Receptores Citoplasmáticos y Nucleares / Gluconeogénesis / Hipoglucemiantes / Hígado Límite: Animals Idioma: En Revista: Drug Metab Dispos Asunto de la revista: FARMACOLOGIA Año: 2021 Tipo del documento: Article
Texto completo
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Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Berberina / Receptores Citoplasmáticos y Nucleares / Gluconeogénesis / Hipoglucemiantes / Hígado Límite: Animals Idioma: En Revista: Drug Metab Dispos Asunto de la revista: FARMACOLOGIA Año: 2021 Tipo del documento: Article